Reference SummaryKucherlapati MH, PLoS One 2013;8(7):e68817

Title

 Genotype directed therapy in murine mismatch repair deficient tumors.

Authors

 Kucherlapati MH; Esfahani S; Habibollahi P; Wang J; Still ER; Bronson RT; Mahmood U; Kucherlapati RS

Journal

 PLoS One

Volume

 8

Issue

 7

Year

 2013

Pages

 e68817

Abstract

 The PI3K/AKT/mTOR pathway has frequently been found activated in human tumors. We show that in addition to Wnt signaling dysfunction, the PI3K/AKT/mTOR pathway is often upregulated in mouse Msh2(-/-) initiated intestinal tumors. NVP-BEZ235 is a dual PI3K/mTOR inhibitor toxic to many cancer cell lines and currently involved in clinical trials. We have treated two mouse models involving Msh2 that develop small intestinal and/or colonic tumors with NVP-BEZ235, and a subset of animals with NVP-BEZ235 and MEK inhibitor ADZ4266. The disease phenotype has been followed with pathology, (18)F FDG PET imaging, and endoscopy. Intestinal adenocarcinomas are significantly decreased in multiplicity by both drug regimens. The majority of tumors treated with combined therapy regress significantly, while a small number of highly progressed tumors persist. We have examined PTEN, AKT, MEK 1&2, MAPK, S6K, mTOR, PDPK1, and Cyclin D1 and find variable alterations that include downregulation of PTEN, upregulation of AKT and changes in its phosphorylated forms, upregulation of pMEK 1&2, p42p44MAPK, pS6K, and Cyclin D1. Apoptosis has been found intact in some tumors and not in others. Our data indicate that NVP-BEZ235 alone and in combination with ADZ4266 are effective in treating a proportion of colorectal cancers, but that highly progressed resistant tumors grow in the presence of the drugs. Pathways upregulated in some resistant tumors also include PDPK1, suggesting that metabolic inhibitors may also be useful in treating these tumors.

Links

 J:204691 – MGI References
23935891 – National Library of Medicine/PubMed

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine - Colon adenocarcinoma
  • Adenovirus carrying cre recombinase
 Intestine - Large Intestine - Colon

observed
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon adenocarcinoma
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Large Intestine - Colon

observed
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon adenocarcinoma - intramucosal
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Large Intestine - Colon

0
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine - Colon adenocarcinoma - intramucosal
  • Adenovirus carrying cre recombinase
 Intestine - Large Intestine - Colon

0
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine - Colon adenoma
  • Adenovirus carrying cre recombinase
 Intestine - Large Intestine - Colon

observed - 100
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon adenoma
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Large Intestine - Colon

observed
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Large Intestine - Colon adenoma Intestine - Large Intestine - Colon

100
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine - Colon adenoma
  • Adenovirus carrying cre recombinase
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Large Intestine - Colon

100
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine - Colon tumor
  • Adenovirus carrying cre recombinase
 Intestine - Large Intestine - Colon

observed
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine adenocarcinoma
  • Adenovirus carrying cre recombinase
 Intestine - Large Intestine

observed
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine adenocarcinoma - intramucosal
  • Adenovirus carrying cre recombinase
 Intestine - Large Intestine

0
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine adenoma
  • Adenovirus carrying cre recombinase
 Intestine - Large Intestine

observed
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine adenoma
  • Adenovirus carrying cre recombinase
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Large Intestine

100
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine neoplasm
  • Adenovirus carrying cre recombinase
 Intestine - Large Intestine

100
[not specified]-Apctm2Rak Msh2tm2.1Rak Intestine - Large Intestine tumor
  • Adenovirus carrying cre recombinase
 Intestine - Large Intestine

100
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine adenocarcinoma Intestine - Small Intestine

observed - high
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine adenocarcinoma
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Small Intestine

observed
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine adenocarcinoma
  • AZD6244 (ARRY-142886)
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Small Intestine

observed
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine adenocarcinoma - intramucosal Intestine - Small Intestine

observed
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine adenocarcinoma - intramucosal
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Small Intestine

0
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine adenocarcinoma - intramucosal
  • AZD6244 (ARRY-142886)
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Small Intestine

0
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine adenoma Intestine - Small Intestine

observed
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine adenoma
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Small Intestine

observed
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine adenoma
  • AZD6244 (ARRY-142886)
  • BEZ235 (NVP-BEZ235-AN)
 Intestine - Small Intestine

observed
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine - Small Intestine tumor Intestine - Small Intestine

100
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine adenoma Intestine

100
[not specified]-Apctm1Rak/+ Intestine adenoma Intestine

100
[not specified]-Apctm1Rak/+ Intestine lesion Intestine

100
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine tumor Intestine

100
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine tumor
  • BEZ235 (NVP-BEZ235-AN)
 Intestine

100
[not specified]-Msh2tm2.1Rak Tg(Vil1-cre)997Gum Intestine tumor
  • AZD6244 (ARRY-142886)
  • BEZ235 (NVP-BEZ235-AN)
 Intestine

100
[not specified]-Msh2tm2.1Rak Intestine tumor
  • Adenovirus carrying cre recombinase
 Intestine

0
C57BL/6J Intestine tumor Intestine

0
C57BL/6J Intestine tumor
  • BEZ235 (NVP-BEZ235-AN)
 Intestine

0